Synthesis and characterization of fac-Re(CO)3-aspartic-N- monoacetic acid: Structural analogue of a potential renal tracer, fac- 99mTc(CO)3(ASMA)

Article abstract of DOI:10.1002/ejic.201200599

The reaction of an aminopolycarboxylate ligand, aspartic-N-monoacetic acid (ASMA), with [Re(CO)₃(H₂O)₃]⁺ was examined. The tridentate coordination of ASMA to this Re^I(CO) ₃ precursor yielded fac-Re(CO)₃(ASMA) as a mixture of diastereomers. The chemistry is analogous to that of the Tc^I(CO) ₃ complex, which yields fac-^99mTc(CO)₃(ASMA) under similar conditions. The formation, structure, and isomerization of fac-Re(CO)₃(ASMA) products were characterized by HPLC, ¹H NMR spectroscopy, and X-ray crystallography. The two major fac-Re(CO) ₃(ASMA) diastereomeric products each have a linear ONO coordination mode with two adjacent five-membered chelate rings, but they differ in the endo or exo orientation of the uncoordinated acetate group, in agreement with expectations based on previous studies. Conditions have been identified for the expedient isomerization of fac-Re(CO)₃(ASMA) to a mixture consisting primarily of one major product. Because different isomeric species typically have different pharmacokinetic characteristics, these conditions may prove useful for the practical isolation of a single ^99mTc(CO) ₃(ASMA) species, thus allowing the isolation of the isomer that has optimal imaging and pharmacokinetic characteristics. This information will aid in the design of future ^99mTc radiopharmaceuticals.

Full text of DOI:10.1002/ejic.201200599

Job/Unit: I20599
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Date: 13-08-12 11:44:21
Pages: 9
FULL PAPER
DOI: 10.1002/ejic.201200599
Synthesis and Characterization of fac-Re(CO) -aspartic-N-monoacetic Acid:
3
9
9m
Structural Analogue of a Potential Renal Tracer, fac- Tc(CO) (ASMA)
3
[a]
[a]
[a]
[b]
Jeffrey Klenc, Malgorzata Lipowska,* Andrew T. Taylor, and Luigi G. Marzilli
Keywords: Rhenium / Aminopolycarboxylate ligands / Ligand design / Isomer resolution / Imaging agents
The reaction of an aminopolycarboxylate ligand, aspartic-N-
exo orientation of the uncoordinated acetate group, in agree-
+
monoacetic acid (ASMA), with [Re(CO)
ined. The tridentate coordination of ASMA to this Re (CO)
precursor yielded fac-Re(CO) (ASMA) as a mixture of dia-
stereomers. The chemistry is analogous to that of the Tc -
3 2 3
(H O) ] was exam- ment with expectations based on previous studies. Condi-
I
3
tions have been identified for the expedient isomerization of
fac-Re(CO) (ASMA) to a mixture consisting primarily of one
3
3
I
major product. Because different isomeric species typically
have different pharmacokinetic characteristics, these condi-
tions may prove useful for the practical isolation of a single
9
9m
(
CO)
similar conditions. The formation, structure, and isomeriza-
tion of fac-Re(CO) (ASMA) products were characterized by
HPLC, H NMR spectroscopy, and X-ray crystallography. The
two major fac-Re(CO) (ASMA) diastereomeric products each
3 3
complex, which yields fac- Tc(CO) (ASMA) under
9
9m
3
3
Tc(CO) (ASMA) species, thus allowing the isolation of the
1
isomer that has optimal imaging and pharmacokinetic char-
acteristics. This information will aid in the design of future
3
9
9m
have a linear ONO coordination mode with two adjacent
Tc radiopharmaceuticals.
five-membered chelate rings, but they differ in the endo or
Introduction
We recently designed, prepared, and evaluated the effi-
cacy of fac-9 Tc(CO) (aspartic-N-monoacetic acid), ab-
9m
3
99m
Rhenium complexes are currently being investigated for breviated as fac- Tc(CO) (ASMA), as a potential new re-
3
[1]
[10]
use as luminescent probes,
central nervous system nal tracer. Note that we have adopted the following nam-
[
2]
[3]
agents, and chemotherapy agents. As a congener of Tc, ing conventions that distinguish the chirality of the ligand:
Re complexes are also commonly employed as structural “Re(CO) (l-ASMA)” refers to a complex with l-ASMA,
3
9
9m
[4]
analogues for
elucidation of
Tc radiotracers. Re analogues allow the whereas “Re(CO) (ASMA)” refers to a complex with any
Tc radiopharmaceuticals, which are other- preparation of ASMA ligand. In order to simplify no-
3
9
9m
wise difficult to characterize owing to the short half-life of menclature, we have omitted the “fac-” prefix and any des-
9
9m
Tc (t1/2 = 6 h) and the tracer level conditions (no carrier ignation of the ligand protonation state (such as ASMAH3
added) of radiopharmaceutical preparations. Methods for or ASMAH) for the remainder of this report.
the preparation of Re complexes have been developed to
We determined that the pharmacokinetic properties of
99m
mirror standard radiolabeling conditions for various
Tc
99m
Tc(CO) (ASMA) in normal rats are comparable to those
3
9
9m
V
[5] 99m III
[6]
complexes, including routes to
Tc O,
Tc O , and
131
131
3
of
I-ortho-iodohippurate ( I-OIH), the radioactive
9
9m
I
[7]
Tc (CO) complexes. The recently improved prepara-
3
standard for measurements of effective renal plasma flow,
I
tion of Re (CO) complexes via the Re precursor, [Re(CO) -
131
3
3
and even superior to I-OIH in rats with simulated renal
[
8]
(H O) ]OTf, has been especially helpful in characteriza-
[9e,10]
2
3
failure.
Thorough structural characterization of
9
9m
tions of several new
potential replacements for the most widely used
tracer,
Tc(CO) renal tracers developed as
99m
3
Tc(CO) (ASMA) is necessary, because the radiotracer
3
9
9m
Tc renal
can exist as any of several distinct isomers. Structural ambi-
guity arises from several factors including the chirality of
the ASMA ligand and the fact that ASMA has more donor
groups (four groups) than available coordination sites on
9
9m
TcO–mercaptoacetyltriglycine (99mTc-MAG3).
[8,9]
the 9 Tc(CO)3 core (three sites). In the absence of struc-
9m
+
tural data, we relied on trends in the ligand chelation mode,
[
[
a] Department of Radiology and Imaging Sciences, Emory
University,
I
established in studies of well-characterized Re (CO) com-
3
1
364 Clifton Rd, Atlanta, GA 30322, USA
plexes with aminopolycarboxylates and other ligands, in or-
Fax: +1-404-727-3488
E-mail: mlipows@emory.edu
der to predict the characteristics of 9 Tc (CO)
9m
I
(ASMA)
3
b] Department of Chemistry, Louisiana State University,
Baton Rouge, LA 70803, USA
such as the chelate ring size, the linear or tripodal coordina-
tion of ASMA, and the likely orientation of uncoordinated
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201200599.
[
8,9,11]
groups.
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J. Klenc, M. Lipowska, A. T. Taylor, L. G. Marzilli
FULL PAPER
Particularly helpful for predicting the major products of stereomers. In order to confirm this prediction, we have
9
9
9m
Tc(CO) (ASMA) was the strikingly similar example, prepared and characterized Re(CO) (ASMA) isomers.
3
3
9m
Tc(CO) (N-carboxymethylmercaptosuccinic
acid)
3
[99m
Tc(CO) (CMSA), Figure 1].
[9d]
Extensive characteriza-
3
tion of its Re analogue, Re(CO) (CMSA), showed that
3
Results and Discussion
9
9m
M(CO) (CMSA) (M =
Tc, Re) exists as a mixture of
3
The synthesis of ASMA as an enantiomerically pure
sample (l-ASMA, 1; or d-ASMA, 3) and as a racemic mix-
ture of d and l isomers (rac-ASMA, 5) has been described
diastereomers. In each isomer, CMSA coordinates as a tri-
dentate ligand, forming two adjacent five-membered chelate
rings in a facial OSO arrangement. The Re(CO) (CMSA)
3
[
12]
previously. Generally, 1 and 3 were synthesized by nucle-
ophilic substitution of bromoacetic acid by using l- or d-
aspartic acid as the nucleophile. The monosubstituted prod-
uct was separated in good yield from unchanged starting
materials, disubstituted byproducts, and excess salt by using
cation exchange chromatography. The synthesis of 5 in ac-
ceptable yield proceeded by Michael addition of glycine to
maleic acid, which eliminated the possibility of disubsti-
tuted products. An excess of maleic acid ensured that the
amino acid starting material was consumed.
diastereomers differ only in the position and orientation of
the uncoordinated acetate group, designated endo when
projecting toward the face defined by the carbonyl ligands,
as in Figure 1, and exo when projecting away from the
tricarbonyl face. Because ASMA and CMSA differ only at
the central heteroatom (N vs. S, respectively), we expected
that M(CO) (ASMA) would also exist as a mixture of dia-
3
Re(CO) (ASMA) complexes were prepared by combin-
3
+
ing 1, 3, or 5 with a slight excess of the [Re(CO) (H O) ]
3
2
3
precursor and maintaining a pH of 6 by using sodium hy-
droxide to replicate conditions for 9 Tc labeling (Figure 2).
Tetramethylammonium hydroxide was also used in the syn-
9m
thesis of Re(CO) (rac-ASMA) in attempts to facilitate
3
crystallization of the product from aqueous solution (see
below). Reaction progress was monitored by HPLC at both
2
0 and 70 °C. The coordination of 1, 3, or 5 to [Re(CO) -
2 3
3
+
(H O) ] proceeded in an identical manner to give mixtures
that differed only owing to the optical activity of the ligand
(ASMA) (M = as expected.
Tc, Re) is expected to be similar to that in M(CO) (CMSA),
which yields a diastereomeric mixture of products with an OXO (X
S, N) coordination mode with two adjacent five-membered che-
Figure 1. Tridentate ligand chelation in M(CO)
3
99m
3
At room temperature and pH = 6, the coordination reac-
tion progressed steadily toward completion over 4 h,
whereas heating at 70 °C pushed the reaction to completion
within 30 min (Figure 3). According to HPLC, treatment of
=
late rings. Each product is expected to be dianionic near physiologi-
cal pH. Only one diastereomer of each complex is shown for sim-
plicity.
+
[Re(CO) (H O) ] with 1 yields two major products, 2A and
3
2
3
I
3
Figure 2. Summary of coordination reactions of l-ASMA [Equation (1)] and d-ASMA [Equation (2)] with the Re (CO) precursor. Each
ligand gives rise to a diastereomeric mixture of products. The racemic mixture (rac-ASMA, 5) gives rise to four products (two dia-
stereomeric pairs of enantiomers 2A/4A and 2B/4B). Note that the enantiomers arise in this way, because the ASMA ligand is a linear
ligand with one end different from the other end. Therefore, for a facial coordination mode, isomerization between an endo and an exo
isomer of an M(CO)
illustrated above.
3
(ASMA) complex for a given ASMA isomer (l or d) by necessity changes the chirality at the metal center, as
2
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fac-Re(CO) -aspartic-N-monoacetic Acid
Figure 3. Progression of the major species formed and present in the reaction mixture (pH = 6) of l-ASMA, 1, with a slight excess of
+
[
Re(CO)
3
(H
2 3
O) ] as assessed by the relative percentage area of HPLC traces. Increasing the reaction temperature from 20 °C (a) to 70 °C
b) significantly accelerated the reaction.
(
2B, named by their order of elution (retention times: 16.3 isomer, 2B. The major products were initially formed in a
and 17.6 min, respectively). Thorough analysis of the char- ratio of 3:1 (2A/2B), but after 1 d at 20 °C the ratio had
acterization data has confirmed that these products are the shifted to 2:1, which indicates that 2A slowly isomerizes to
exo (2A) and endo (2B) diastereomers of Re(CO) (ASMA) 2B under these conditions. Heating of the reaction mixture
3
shown in Figure 2, Equation (1). The intermediates ob- accelerates both the formation and isomerization reactions,
served during the reaction with relatively short retention as evidenced by a roughly 2:1 ratio of 2A/2B obtained after
times (4–8 min) are likely monodentate or bidentate com- just 5 min at 70 °C (Figure 3b). HPLC chromatograms to-
1
plexes (see Supporting Information). Two minor products gether with the H NMR spectra of the samples before and
with a retention time of ca. 14 min persist at room tempera- after isomerization showed no difference in product ratios,
ture, but quickly and completely convert to the major prod- which indicates that the ratio of isomers is not significantly
ucts 2A and 2B after heating for 1 h. Although these inter- affected by the HPLC method. To examine this isomeriza-
mediates could not be isolated, we believe they are Re(CO)3- tion further, a small aliquot of the product mixture (after
(ASMA) isomers with one five- and one six-membered che- 24 h at 20 °C, pH = 6, 2:1 ratio of 2A/2B) was divided into
late ring. Previous studies demonstrated that six-membered six fractions. The temperature and pH of each sample was
NO chelate rings are energetically less favorable and form varied, and the conversion of 2A to 2B was monitored by
more slowly than five-membered chelate rings.[ Hence we HPLC (Figure 4). For conditions under which the isomer-
expect that complexes with both a five- and a six-membered ization reached equilibrium quickly (70 °C, pH Ն 7), the
NO chelate ring will be present only in small amounts and final ratio of 2A/2B was ca. 1:9. The robustness of 2A and
will readily convert to products with two five-membered 2B was not particularly examined in this study, although
13]
chelate rings, as is observed.
the complexes were chemically stable over periods of up to
Identical HPLC chromatograms were observed when 7 d under the various conditions used in the isomerization
9
9m
using either 3 or 5 as the ligand. However, for Re(CO) (rac- study. HPLC analysis of the metabolites of
Tc(CO)3-
3
[
9e]
ASMA), each peak now represents an enantiomeric mixture (ASMA) in our parallel study shows that the complex is
of isomers, which leads to the presence of four major prod- long-lived in biological systems.
ucts in the final reaction mixture: Re(CO) (l-ASMA) dia-
From Figure 4, it is clear that both heat and pH have a
3
stereomers 2A and 2B and their Re(CO) (d-ASMA) distinct effect on the isomerization of the product mixture.
3
enantiomers 4A and 4B [Figure 2, Equation (2)].
Without the benefit of heat or elevated pH (20 °C, pH = 4),
Figure 3a shows that over the course of 1 d at 20 °C and the initial product ratio of 2:1 is relatively constant. How-
pH = 6, the product ratio gradually shifts toward the endo ever, raising the pH to 9 at 20 °C accelerates the isomeriza-
Figure 4. The initial reaction at 20 °C and pH = 6 for 1 d yielded a mixture of two Re(CO)
The product ratio of the crude reaction mixture was studied by monitoring the percentage area from the HPLC trace for up to 7 d at
0 °C (a) and 70 °C (b) for pH = 4, 7, and 9.
3
(l-ASMA) isomers, 2A (exo) and 2B (endo).
2
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J. Klenc, M. Lipowska, A. T. Taylor, L. G. Marzilli
FULL PAPER
tion only slightly. Similarly, heating under acidic conditions
The crystallization of K[endo-Re(CO) (rac-ASMA)] was
3
(70 °C, pH = 4) is not practical for rapid isomerization, and achieved from a concentrated aqueous pH = 2 solution of
the products approach equilibrium only after 7 d. Thus, to the equilibrated product. Slow concentration of this sample
promote expedient isomerization to the thermodynamic yielded small, colorless crystals as a mixture of enantiomers
product, 2B, heating under neutral or slightly basic condi- 2B and 4B, with the uncoordinated carboxyl group proton-
tions is required (70 °C, pH Ն 7). Although a thorough ated (Figure 5a). Attempts under similar conditions and at
mechanistic study of this multistep isomerization process is pH = 6 to obtain crystals with a more hydrophobic counter-
beyond the scope of this project, the acceleration of the ion, Me N[endo-Re(CO) (rac-ASMA)], or the exo enantio-
4
3
reaction as pH increases strongly indicates that the initial mers, Me N[exo-Re(CO) (rac-ASMA)] or K[exo-Re(CO) -
4
3
3
step is the deprotonation of the NH group by hydroxide (rac-ASMA)], were unsuccessful. To confirm that the crys-
ions to generate a small equilibrium amount of deproton- tals obtained corresponded to the thermodynamic isomer,
ated complex. We hypothesize that the strongly donating N- a small crystal was dissolved and analyzed by HPLC. The
donor thereby created will favor the formation of a five- only major peak corresponded to 2B, and this peak con-
coordinate, short-lived intermediate to yield two closely re- tained Ͼ95% of the trace area. X-ray structural analysis
lated intermediates with either one of the two carboxyl shows that the enantiomers 2B and 4B (2B presented in
groups dissociated. Collapse of either intermediate to regen- Figure 5a) are indeed the endo isomers, K[endo-Re(CO)3-
erate the six-coordinate complex would lead to either the (rac-ASMA)], as predicted from results for the thermo-
[
9a]
endo or exo isomer, depending on the direction in which the dynamic product of Re(CO) (CMSA). In the pseudo-oc-
3
carboxyl group moves to close the chelate ring.
tahedral complex, the coordinated tridentate ASMA ligand
The identification of the kinetic isomer (2A) and the is bound in a facial ONO arrangement, which gives rise to
thermodynamic isomer (2B) enables the assignment of these two adjacent five-membered NO chelate rings. The dan-
products to a specific diastereomer. The energetically most gling protonated carboxyl group is facing away from the
favorable arrangement (thermodynamic isomer 2B) will triangular ONO face as expected for the endo isomer. The
–
likely have the bulky dangling –CH CO group facing away bond lengths between donor groups and the metal core
2
2
(endo) from the crowded chelate rings formed by the triden- (Re1–O4, Re1–O6, Re1–N1) are consistent with previous
tate ASMA ligand (Figure 5a). Furthermore, the dangling examples for carboxyl and amino donor groups
[
8,14]
carboxylate group (at pH = 6) will be negatively charged (Table 1).
Deviations from the expected geometry occur
and electrostatically repelled from the negatively charged in- systematically between analogous bond angles of
I
ner coordination sphere, which makes the endo isomer ther- Me N[endo-Re(CO) (CMSA)] and those of other Re (CO)
4
3
3
[
9c,9d]
modynamically more favorable. Because the thermodynami- complexes that share a similar coordination mode.
The
cally favored product is likely to be the endo isomer and crystal structure confirms our assignment of thermo-
because this isomer should be even more favored at high dynamic isomers 2B and 4B as endo-Re(CO) (ASMA).
3
pH, we can make an initial structural assignment of 2B as
The explicit characterization of 2B supports our assign-
1
endo-Re(CO) (ASMA). Comparisons with the H NMR ment of 2A based on isomerization between the two prod-
3
spectrum and the crystal structure of Re(CO) (CMSA) sup- ucts. However, the structure of 2A remains somewhat am-
3
port this assignment and, consequently, the assignment of biguous, because in addition to the expected exo-Re(CO)3-
2
A (and 4A) as exo-Re(CO) (ASMA).
(ASMA) product (Figure 5b), isomers with the β-carboxyl
3
3
Figure 5. (a) ORTEP representation of one enantiomer (from l-ASMA) of the anion of K[endo-Re(CO) (rac-ASMA)], 2B. Hydrogen
+
atoms are shown in their calculated positions. The K ion is omitted for clarity. (b) Model of exo-Re(CO)
3
(l-ASMA) (2A) calculated by
using the MM2 force field[ to illustrate the exo orientation of the dangling acetate group.
18]
4
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fac-Re(CO) -aspartic-N-monoacetic Acid
I
Table 1. Selected bond lengths [Å] and angles [°] for Re (CO)
plexes with ASMA and CMSA.[
3
com-
a]
3 4 3
K[endo-Re(CO) (rac-ASMA)] Me N[endo-Re(CO)
(CMSA)][9d]
Distances
Re1–C1
Re1–C2
Re1–C3
Re1–O4
Re1–N1
Re1–O6
1.889(4)
1.906(4)
1.914(4)
2.135(2)
2.201(3)
2.138(2)
5.466
Re1–C3
Re1–C1
Re1–C2
Re1–O6
Re1–S1
Re1–O4
1.897(4)
1.913(4)
1.927(4)
2.127(2)
2.452(1)
2.164(2)
5.824
[
[
b]
[b]
C7–C9
C4–C9
C4–C9
C6–C9
b]
[b]
3.842
3.005
Angles
3
Figure 6. Conceivable isomers of Re(CO) (ASMA) with the β-carb-
oxyl group coordinated to the metal core. Enantiomers of the iso-
mers shown would also exist, but are not pictured. For clarity, the
complexes are shown without formal charges or counterions. Lin-
early coordinated isomers contain adjacent five- and six-membered
chelate rings, whereas tripodal isomers contain a seven-membered
ring.
C1–Re1–N1 98.43(13)
C1–Re1–C2 88.20(15)
C1–Re1–C3 90.03(15)
C1–Re1–O4 93.91(13)
C2–Re1–N1 97.62(13)
C2–Re1–O6 96.54(12)
C2–Re1–C3 88.75(15)
C3–Re1–O6 93.58(12)
C3–Re1–O4 97.89(12)
O6–Re1–N1 75.50(10)
O6–Re1–N1 77.51(10)
O4–Re1–O6 80.97(10)
C2–Re1–O4 173.02(12)
C1–Re1–O6 174.09(12)
C3–Re1–N1 169.54(12)
C3–Re1–S1 95.86(11)
C3–Re1–C1 89.23(14)
C3–Re1–C2 88.30(15)
C3–Re1–O6 95.92(12)
C1–Re1–S1 94.89(12)
C1–Re1–O4 90.78(11)
C1–Re1–C2 91.17(16)
C2–Re1–O4 95.92(12)
C2–Re1–O6 93.33(13)
O4–Re1–S1 79.94(6)
O6–Re1–S1 80.29(7)
O4–Re1–O6 83.76(8)
C1–Re1–O6 173.25(12)
C3–Re1–O4 175.78(13)
C2–Re1–S1 172.69(12)
clude an amino proton (NH), H , two protons from the
α
coordinated N-carboxymethyl group (exo- and endo-
HCOORD), and two Hβ protons from the uncoordinated
acetate group, none of which are magnetically equivalent
(Table 2). Each signal shows a splitting pattern that is con-
sistent with the predicted coordination mode.
[
a] Although the atom labels of each complex are inconsistent (lab-
eled according to the appropriate CCDC file), each row lists an
analogous length or angle. [b] Nonbonded distances between carb-
oxyl group carbon atoms.
group (as labeled in Figure 1) coordinated to the metal core
are possible (Figure 6). In a tripodal coordination mode,
the ligand will form three chelate rings (one five-, one six-,
and one seven-membered ring) with the metal core; such an
arrangement has been shown to be unfavorable compared
[
11a]
to that of 2B.
Potential isomers with ASMA bound lin-
early through the β-carboxyl group will form two adjacent
chelate rings (one five- and one six-membered ring), which,
although more likely to form than tripodal isomers, are less
stable and form more slowly than 2A because of its six-
membered chelate ring. Therefore, it is very unlikely that
1
Figure 7. H NMR spectra (D
2
O, 20 °C, pH = 6) of Re(CO)
3
(l-
ASMA) maintained at 20 °C (I) and after heating at 70 °C for 3 d
isomers with a coordinated β-carboxyl group will be major (II) are shown (detailed in Table 2). The signals from exo-Re(CO)3-
(
3
l-ASMA) (2A) and endo-Re(CO) (l-ASMA) (2B) can be decon-
products of the reaction mixture of Re(CO) (ASMA).
3
voluted by comparing the two spectra. Selected signals from 2A (I)
and 2B (II, marked with an *) are labeled to highlight significant
differences.
However, as noted earlier, the isomers forming adjacent
five- and six-membered chelate rings are likely the minor
products that readily convert to 2A and 2B, as observed by
HPLC.
1
Comparisons of the H NMR signals of H , NH, and
α
Further confirmation of the structure of 2A is possible HCOORD of 2A and 2B (Figure 7; these protons are bonded
1
through H NMR spectroscopy. When both major products to C5, N1, and C6, respectively; Figure 5) are especially
1
2
A and 2B are present in nearly equal amounts, the H helpful for confirming the structure of 2A. Perhaps most
NMR spectrum is difficult to interpret owing to the similar- enlightening are differences in the shielding of H in endo-
α
ity in peak intensity and some overlap in peaks from the Re(CO) (ASMA) and exo-Re(CO) (ASMA). Data from
3
3
two sets (Figure 7, I). In the equilibrated sample (as detailed our previous work (Table 3) suggest that protons in an exo
above), two sets of signals in a 1:9 ratio (2A/2B) are easily orientation (away from the tricarbonyl face) are more
distinguishable (Figure 7, II). Each resonance was assigned shielded than those in an endo orientation, which results in
1
to the appropriate diastereomer by comparing the two spec- an upfield shift of the H NMR signal. The orientation of
tra, as shown in Figure 7. The expected signals for Re(CO)3- the uncoordinated group can be inferred from the shift of
(
ASMA) isomers are observed in each spectrum; these in- H , as these two groups must assume opposing orientations.
α
Eur. J. Inorg. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: I20599
/KAP1
Date: 13-08-12 11:44:21
Pages: 9
J. Klenc, M. Lipowska, A. T. Taylor, L. G. Marzilli
FULL PAPER
1
(l-ASMA)]2– anion.
3
Table 2. H NMR spectroscopic data (D
2
O, pH = 6) for 2A (exo) and 2B (endo) isomers of the [Re(CO)
2B (endo)
1H NMR signal
2A (exo)
NH
6.42 (m, 1 H)
4.12 (m, 1 H, J = 5.6, 8.8 Hz)
2.79 (dd, 1 H, J = 5.6,16.4 Hz)
6.18 (d, 1 H, J = 6.8 Hz)
3.63 (dd, 1 H, J = 6.0, 8.0 Hz)
2.70 (d, 2 H, J = 6.0 Hz)
2.70 (d, 2 H, J = 8.0 Hz)
3.93 (dd, 1 H, J = 6.8, 17.2 Hz)
3.67 (d, 1 H, J = 17.2 Hz)
H
H
α
β
2.55 (dd, 1 H, J = 8.8,16.4 Hz)
endo-HCOORD
exo-HCOORD
3.58 (m, 2 H)
The H signal in 2B (δ = 3.63 ppm) is significantly upfield
In addition, we expect the uncoordinated acetate group
α
of that of 2A (δ = 4.12 ppm). Therefore, H of 2A must to shield the adjacent amine proton (NH) relative to its spa-
α
assume the endo orientation, as in exo-Re(CO) (ASMA).
tial proximity. In endo-Re(CO) (ASMA) (see crystal struc-
3
3
ture of 2B in Figure 5a), the uncoordinated CH CO H
group will be closer to the amino proton, which causes the
2
2
1
Table 3. Comparison of H NMR shifts (ppm) of exo- and endo-
I
proton signals in various Re (CO)
generally deshielded compared to analogous exo protons.
3
complexes; endo protons are NH group to be more shielded and hence shifts the re-
1
sulting H NMR signal upfield (δ = 6.18 ppm) relative to
Compound
Re(CO) (ASMA)
endo-Re(CO) (ASMA)
1H NMR signal
endo
exo
the analogous NH signal (δ = 6.42 ppm) from exo-Re(CO)3-
(ASMA) (Table 2).
3
H
H
H
H
α
4.12
3.93
3.97
3.49
5.45
5.75
3.63
3.67
3.50
3.23
5.03
5.17
3
COORD
[
a]
Re(CO)
Re(CO)
Re(CO)
Re(CO)
3
3
3
3
(CMSA)
α
[
b]
(CCM)
(ENDAC)
α
[
c]
N-H
N-H
Conclusions
[
d]
(DTA)
a] CMSA[9d] = carboxymethylmercaptosuccinic acid. [b] CCM
[8]
We have prepared Re(CO) (ASMA) as an analogue of
3
[
[9c]
99m
=
S-(carboxymethyl)-l-cysteine. [c] ENDAC = ethylenediamine- a potential new renal tracer,
Tc(CO) (ASMA), through
3
[9b]
N,NЈ-diacetic acid. [d] DTA
= diethylenetriamine-N-acetic acid.
99m
methods that mimic
Tc(CO) labeling procedures. We
3
demonstrated, by monitoring the reaction progress, that the
The splitting pattern of the NH signals provides ad- major products formed are analogous to those observed
ditional support for the structural assignment of 2A. NH during the preparation of 9 Tc(CO) (ASMA). As pre-
9m
3
has three neighboring protons (Hα and exo- and endo- dicted on the basis of previously characterized M(CO) (M
3
9m
H
), which are likely to contribute to the splitting of = Re, 9 Tc) complexes, the major isomers of M(CO)3-
COORD
1
its H NMR signal. In each diastereomer (2A and 2B), the (ASMA) have a facial, tridentate, ONO coordination mode
NH proton is in an endo orientation, which allows straight- with ASMA, which forms two adjacent five-membered che-
forward comparisons of signal splitting owing to the rela- late rings. Coordination of either l-ASMA or d-ASMA
tive spatial arrangement of neighboring protons. As we ob- yields a mixture of two diastereomeric complexes that differ
served earlier, the orientation of H is opposite to that of only in the position and orientation of the uncoordinated
α
–
the uncoordinated acetate group. Thus, the NH signal in acetate group (–CH CO ) on the aspartate chelate ring.
2
2
endo-Re(CO) (ASMA) (2B) can be split by exo-H , exo- The detailed characterization of Re(CO) (ASMA) isomers
3
α
3
HCOORD, and endo-HCOORD (see Figure 5), whereas the NH reinforces trends regarding the coordination of aminopoly-
I
signal in exo-Re(CO) (ASMA) can be split by endo-H , carboxylate ligands to the M (CO) core, such as preferred
3
α
3
exo-HCOORD, and endo-HCOORD. This difference is signifi- donor groups, chelate ring size, and coordination mode.
cant, because – according to the crystal structure of 2B – By examining the isomerization of the diastereomeric
both the exo-HCOORD and exo-H protons in 2B have tor- products by HPLC we have identified endo-Re(CO)3-
α
sion angles near to 90° with NH (exo-HCOORD–C6–N1–H (ASMA) (2B or 4B) as the thermodynamically favored
9
4.3° and exo-H –C5–N1–H 89.3°), which results in a cou- product and exo-Re(CO) (ASMA) (2A or 4A) as the kinet-
α
3
pling constant of essentially zero (Figure 5a). Consequently, ically favored product. We also monitored the isomerization
in 2B only coupling between NH and endo-HCOORD is ob- of Re(CO) (ASMA) and outlined conditions for a practical
3
served, which results in a distinct doublet at δ = 6.18 ppm. isomerization that favor the thermodynamic product in a
For exo-Re(CO) (ASMA), we expect to see NH splitting 9:1 ratio. This result has proved to be useful in NMR stud-
3
from both endo-Hα and endo-HCOORD and assume that ies and to obtain X-ray quality crystals. Because different
splitting from exo-HCOORD is not observed because of a isomeric species typically have different pharmacokinetic
nearly orthogonal torsion angle with NH, similar to that characteristics, the ability to control the endo/exo ratio may
observed in 2B. The NH splitting in 2A matches this expec- allow the approximate isolation of a single 9 Tc(CO)3-
tation and resembles a triplet (δ = 6.42 ppm), which sug- (ASMA) species, thus enhancing the effect of the isomer
gests that the coupling constants with Hα and endo- with optimal imaging and pharmacokinetic characteristics.
9m
HCOORD are similar. This allows us to confirm the assign- In addition, the characterization of 9 Tc(CO) (ASMA)
9m
3
ment of 2A (and 4A) as exo-Re(CO) (ASMA).
through Re analogues will allow subsequent evaluation of
3
6
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Job/Unit: I20599
/KAP1
Date: 13-08-12 11:44:21
Pages: 9
3
fac-Re(CO) -aspartic-N-monoacetic Acid
the pharmacokinetic properties to be correlated to its struc- 1H NMR spectrum showed two sets of peaks in ca. 1:1 ratio. The
mixture of isomers was heated at 70 °C for 2 d to isomerize the
mixture to favor 2B, (2A/2B, 1:5). Differences in spectra before and
after isomerization were used to determine which signals were de-
tural features, which will help to guide the design of poten-
9
9m
tial new
Tc radiopharmaceuticals.
rived from each isomer.
1
2
8
A: H NMR (D
2
O, pH = 6): δ = 6.42 (m, 1 H), 4.12 (m, J = 5.6,
Experimental Section
.8 Hz, 1 H), 3.55 (m, 2 H), 2.78 (dd, J = 5.6, 16.4 Hz, 1 H), 2.55
General Procedures: All reagents and solvents were purchased as
reagent grade and used without further purification. Aspartic-N-
monoacetic acid (ASMA) was synthesized as previously reported
(
dd, J = 8.8, 16.4 Hz, 1 H) ppm.
1
2
B: H NMR (D
2
O, pH = 6): δ = 6.18 (d, J = 6.8 Hz, 1 H), 3.93
(dd, J = 6.8, 17.2 Hz, 1 H), 3.67 (d, J = 17.2 Hz, 1 H), 3.63 (dd, J
[12e]
as both the racemic mixture
and the optically active l iso-
=
1
6.0, 8.0 Hz, 1 H), 2.69 (d, J = 8.0 Hz, 1 H), 2.68 (d, J = 6.0 Hz,
H) ppm.
mer,[
12a]
briefly described below. Triaquatricarbonyl-rhenium(I) tri-
fluoromethanesulfonate was prepared as previously reported and
used as a 0.1 m stock solution.[8] Gel filtration was performed on
Sephadex G-15 beads, eluted with deionized water at a rate of
D-(N-Carboxymethyl)aspartic Acid (3, D-ASMA): d-ASMA (3) was
prepared similarly to 1, by using d-aspartic acid instead of l-
aspartic acid. The product was purified by using ion exchange
chromatography to yield 3 (0.105 g, 55%) as a colorless oil. The
0
.5 mL/min. Ion exchange chromatography was performed with
+
Dowex 50WX4 resin in the H form. The products were washed
with water, then eluted with 0.5 m NH OH. H NMR spectra were
4
1
13
20
1
H and C NMR spectra were identical to those of 1. [α]D = –10.2
+
(
c = 1.0, H
found 192.05014.
Re(CO) -ASMA) (4): The reaction of d-ASMA (0.075 g,
0.39 mmol, 5 mL) with [Re(CO) (H O) ]OTf (0.27 mmol, 0.1 m,
2 6 6
O). HRMS (ESI): calcd. for C H10NO [M] 192.05026;
obtained at room temperature in deuterium oxide with a 400 MHz
Varian NMR spectrometer. All chemical shifts were referenced to
the water peak in D
2
O (δ = 4.80 ppm). HRMS data was measured
3
(D
by the Emory University Mass Spectrometry Center by using a
Thermo Finnigan LTQ-FTMS. HPLC analyses were performed
with a Waters Breeze system equipped with a Waters 2487 dual
wavelength absorbance detector, Waters 1525 binary pump, XTerra
MS C18 column (5 μm; 4.6ϫ250 mm), and using a flow rate of
3
2
3
2.7 mL) proceeded in a manner identical to that used to prepare 2
to yield a white solid (0.085 g, 69%). The H NMR spectrum was
identical to that of 2. HRMS (ESI): calcd. for C
[M] 459.96839; found 459.96857.
1
1
87
9
H
7
NO
9
Re
–
1
0
mL/min gradient method described previously, with aqueous
(
؎)-(N-Carboxymethyl)aspartic Acid (5, rac-ASMA): This com-
.05 m triethylammonium phosphate buffer, pH = 2.5, as solvent A
[12e]
pound was synthesized as previously reported.
0.075 g, 1.0 mmol) and maleic acid (0.128 g, 1.1 mmol) were com-
bined in 10 mL of water. The pH of this mixture was adjusted to
1 with 1 m aqueous potassium hydroxide. The solution was heated
Briefly, glycine
[9a]
and methanol as solvent B. Elemental analyses were performed
by Atlantic Microlabs, Atlanta, GA. Optical rotation was measured
at 589 nm with a Perkin–Elmer 541 polarimeter.
(
1
L
-(N-Carboxymethyl)aspartic Acid (1,
L
-ASMA): l-ASMA (1) was
Briefly, l-aspartic acid (0.13 g,
.0 mmol) and bromoacetic acid (0.14 g, 1.0 mmol) were neutral-
to approximately 70 °C for 1 d. The pH was adjusted to 2 with
concentrated HCl, and the mixture was cooled to 0 °C to precipi-
tate KCl and starting materials. The filtrate was concentrated to
yield a white solid (0.164 g) that contained some KCl. The elabo-
rate purification method employed for 1 produced 5 (0.077 g, 40%)
prepared as previously reported.[
1
12a]
ized separately in water with 1 m NaOH (2 mL, 2.0 mmol) and
combined. The resulting solution (10 mL) was heated to 70 °C. The
pH was maintained at 11 by frequent addition of 1 m NaOH, total-
ing 4.0 mL. No base was added after 1 h, and the solution was
heated for an additional 2 h without any change in the pH. The
pH was adjusted to 2 by using concentrated HCl, and any salt
that crystallized was removed by filtration. The crude product was
purified by using ion exchange chromatography to yield 1 (0.127 g,
1
in high purity for H NMR and HRMS analyses; however, the
1
crude product was sufficiently pure for use in the next step. The H
NMR spectrum agreed with that of the previously reported com-
1
pound. H NMR (D
2
O, pH 6): δ = 3.84 (dd, J = 4.4, 7.6 Hz, 1 H),
3.70 (d, J = 16.4 Hz, 1 H), 3.64 (d, J = 16.4 Hz, 1 H), 2.83 (dd, J
1
3
= 4.0, 17.6 Hz, 1 H), 2.75 (dd, J = 7.6, 17.6 Hz, 1 H) ppm.
NMR (D O, pH 3): δ = 37.5, 51.3, 61.7, 174.3, 175.7, 178.9 ppm.
= 0.0 (c = 1.0, H O). HRMS (ESI): calcd. for C NO
[M] , 190.03571; found 190.03565.
C
1
[12a]
[12b]
6
6%) as a colorless oil. H NMR
matched those of the previously reported compound. 1H NMR
O, pH = 4): δ = 3.89 (dd, J = 3.2, 4.4 Hz, 1 H), 3.72 (d, J =
0.8 Hz, 1 H), 3.64 (d, J = 10.8 Hz, 1 H), 2.91 (dd, J = 3.2, 12.0 Hz,
and optical rotation
data
2
20
[α]
D
2
6
H
8
6
–
(D
2
1
Re(CO) (rac-ASMA) (2 and 4): To an aqueous solution of crude 5
3
1
=
=
H), 2.85 (dd, J = 4.4, 12.0 Hz, 1 H) ppm. 13C NMR (D
2): δ = 37.5, 51.6, 61.3, 173.9, 175.3, 177.6 ppm. [α]
2
O, pH (0.034 m, 0.068 mmol, 2 mL) was added Me NOH·5H O (0.038 g,
4
2
2
0
D
= +4.0 (c
N [M] 192.05026;
3 2 3
0.21 mmol) and [Re(CO) (H O) ]OTf (0.068 mmol, 0.1 m,
+
1.0, H
2
O). HRMS (ESI): calcd. for C
6
H
10
O
6
0.68 mL), and the solution was heated at 70 °C for 30 min. HPLC
analysis of the reaction mixture was identical to that of 2, with two
peaks with retention times of 16.3 min (2A and 4A) and 17.3 min
found 192.05003.
Re(CO) -ASMA) (2): An aqueous solution of l-ASMA (0.020 g,
.1 mmol, 5 mL) was neutralized with 1 m NaOH (0.1 mL,
.1 mmol) and added to a stirred solution of [Re(CO) (H O) ]OTf
3
(L
(
2B and 4B) in a ca. 2:1 ratio. The reaction mixture was concen-
0
0
trated to 1 mL, and the products were purified by using gel fil-
3
2
3
tration as described above for 2 to yield the products as a white
(0.1 mmol, 0.1 m, 1.0 mL, OTf = trifluoromethanesulfonate). The
1
solid (0.031 g, 75%). H NMR and HRMS data were identical to
reaction mixture was heated at 70 °C for 30 min. Aqueous NaOH
was added as needed to maintain the pH at 6. HPLC analysis of
the reaction mixture revealed two peaks with retention times of
the data for 2 and 4. The product was equilibrated (70 °C, pH = 7,
1
d), and the endo-product was crystallized from a concentrated
aqueous solution (pH = 2) at room temperature as a potassium
16.3 min (2A) and 17.3 min (2B) in a 2:1 ratio. The reaction mixture
salt (the K+ cation is present in the crude starting material, 5).
was concentrated to 1 mL, and the products were purified by gel
filtration. The UV-active fractions were analyzed by HPLC, and
those without impurity were combined and concentrated under re-
duced pressure to yield a white solid (0.019 g, 38%). HRMS (ESI):
C
2
9
H
7
KNO
1.74, H 1.35, N 2.81.
Crystal Structure of K[endo-Re(CO)
tal was coated with Paratone N oil, suspended in a small fiber loop,
9
Re (498.46): calcd. C 21.69, H 1.42, N 2.81; found C
3
(rac-ASMA)]: A suitable crys-
187
Re [M]– 459.96839; found 459.96846. The
calcd. for C
9
H
7
O
9
N
Eur. J. Inorg. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 13-08-12 11:44:21
Pages: 9
J. Klenc, M. Lipowska, A. T. Taylor, L. G. Marzilli
FULL PAPER
placed in a cooled nitrogen gas stream at 173 K. and analyzed with
a Bruker D8 APEX II CCD sealed tube diffractometer with graph-
[1] K. Lo, K. Zhang, S. Li, Eur. J. Inorg. Chem. 2011, 3551–3568.
ite-monochromated Mo-K
measured by using a series of combinations of φ and ω scans with
0 s frame exposures and 0.5° frame widths. Data collection, in-
dexing, and initial cell refinements were all performed with APEX
α
(λ = 0.71073 Å) radiation. Data were [2] A. S. Louie, N. Vasdev, J. F. Valliant, J. Med. Chem. 2011, 54,
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3] S. P. Fricker, R. M. Mosi, B. R. Cameron, I. Baird, Y. Zhu, V.
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McKerrow, J. Inorg. Biochem. 2008, 102, 1839–1845.
1
[
15]
II
software. Frame integration and final cell refinements were
[15]
done by using SAINT
software. The final cell parameters were
[
4] a) E. García Garayoa, D. Rüegg, P. Bläuenstein, M. Zwimpfer,
I. Khan, V. Maes, A. Blanc, A. G. Beck-Sickinger, D. A.
Tourwé, P. A. Schubiger, Nucl. Med. Biol. 2007, 34, 17–28; b)
T. Esteves, C. Xavier, S. Gama, F. Mendes, P. D. Raposinho, F.
Marques, A. Paulo, J. C. Pessoa, J. Rino, G. Viola, I. Santos,
Org. Biomol. Chem. 2010, 8, 4104–4116; c) M. Sagnou, D. Be-
naki, C. Triantis, T. Tsotakos, V. Psycharis, C. P. Raptopoulou,
I. Pirmettis, M. Papadopoulos, M. Pelecanou, Inorg. Chem.
determined from least-squares refinement on 4395 reflections. The
structure was solved by using direct methods and difference Fourier
techniques (SHELXTL, V6.12).[ Hydrogen atoms were placed in
their expected chemical positions by using the HFIX command
and were included in the final cycles of least-squares with isotropic
16]
U
ij values related to the atoms ridden upon. All non-hydrogen
atoms were refined anisotropically. Scattering factors and anoma-
2011, 50, 1295–1303.
lous dispersion corrections were taken from the International
Tables for X-ray Crystallography.[17] Structure solution, refinement,
[5] a) U. Abram, M. Braun, S. Abram, R. Kirmse, A. Voigt, J.
Chem. Soc., Dalton Trans. 1998, 231–238; b) H. H. Nguyen,
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gemann, U. Abram, Inorg. Chem. 2009, 48, 9356–9364.
graphics, and generation of publication materials were performed
by using SHELXTL, V6.12 software. These results are summarized
in Table 4. CCDC-884591 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[
6] M. Toganoh, S. Ikeda, H. Furuta, Chem. Commun. 2005, 4589–
4591.
[7] R. Alberto, J. Kyong Pak, D. van Staveren, S. Mundwiler, P.
Benny, Pept. Sci. 2004, 76, 324–333.
[
[
8] H. He, M. Lipowska, X. Xu, A. T. Taylor, M. Carlone, L. G.
Marzilli, Inorg. Chem. 2005, 44, 5437–5446.
9] a) H. He, M. Lipowska, X. Xu, A. T. Taylor, L. G. Marzilli,
Inorg. Chem. 2007, 46, 3385–3394; b) M. Lipowska, H. He, X.
Xu, A. T. Taylor, P. A. Marzilli, L. G. Marzilli, Inorg. Chem.
Table 4. Additional details of the data collection and structure re-
finement of K[endo-Re(CO) (rac-ASMA)].
3
2B and 4B
2
010, 49, 3141–3151; c) M. Lipowska, R. Cini, G. Tamasi, X.
Xu, A. T. Taylor, L. G. Marzilli, Inorg. Chem. 2004, 43, 7774–
783; d) H. He, M. Lipowska, A. M. Christoforou, L. G. Mar-
Empirical formula
Formula mass
T [K]
C
9
H
7
KNO Re
9
498.46
173(2)
0.71073
7
zilli, A. T. Taylor, Nucl. Med. Biol. 2007, 34, 709–716; e) M.
λ [Å]
Lipowska, J. Klenc, L. G. Marzilli, A. T. Taylor. J. Nucl. Med.
Crystal system
Space group
Unit cell dimensions
a [Å]
b [Å]
c [Å]
monoclinic
P2 /c
2012. DOI: 10.2967/jnumed.111.102236.
1
[
10] M. Lipowska, J. Klenc, E. Malveaux, L. Marzilli, A. Taylor, J.
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7.952(4)
14.774(7)
10.879(5)
98.417(7)
1264.4(10)
4
[
1
0625–10634; b) G. Makris, O. Karagiorgou, D. Papagianno-
β [°] 3
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Psycharis, M. Pelecanou, I. Pirmettis, M. S. Papadopoulos,
Eur. J. Inorg. Chem. 2012, 3132–3139.
V [Å ]
Z
ρ
calcd. [mg/m3]
2.619
9.988
–1
[12] a) R. V. Snyder, R. J. Angelici, J. Inorg. Nucl. Chem. 1973, 35,
Absorption coefficient [mm ]
R indices [IϾ2σ(I)]
5
1
2
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33–142; c) T. Miyazawa, Bull. Chem. Soc. Jpn. 1980, 59, 2555–
565; d) K. Takahashi, T. Nakahama, JP 07–089913, 1995; e)
R
wR
1
= 0.0260
2
= 0.0590
J. A. R. Hartman, R. P. Woodbury, US 5,362,412, 1994.
13] M. Lipowska, A. T. Taylor, L. G. Marzilli in Technetium and
other radiometals in chemistry and medicine (Eds.: U. Mazzi,
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Supporting Information (see footnote on the first page of this arti-
cle): HPLC chromatograms showing the final products and their
isomerization along with data tables for Figures 3 and 4.
[
[
[
Acknowledgments
15] Bruker APEX2, Program Suite for Crystallographic Software,
Bruker AXS Inc., Madison, 2003.
This work was supported by the National Institutes of Health/
National Institute of Diabetes and Digestive and Kidney Diseases [16] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
[
17] International Tables for X-ray Crystallography, vol. C (Ed.:
A. J. C. Wilson), Academic Publishers, Dordrecht, 1992.
18] Chem. 3D Pro, Desktop Modelling Application Suite, Cam-
bridgeSoft, Cambridge, MA, 2010.
(Grant No. R37 DK38842). The authors thank Dr. Kenneth
Hardcastle of Emory University for discussions regarding crystal
preparation and for the structure determination. We also thank
Dr. Patricia A. Marzilli for her invaluable comments during the
preparation of the paper.
[
Received: May 31, 2012
Published Online: ᭿
8
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Eur. J. Inorg. Chem. 0000, 0–0

Job/Unit: I20599
/KAP1
Date: 13-08-12 11:44:21
Pages: 9
3
fac-Re(CO) -aspartic-N-monoacetic Acid
Tricarbonylrhenium(I) Complexes
Rhenium complexes that are structural
analogues for potential technetium renal
tracers are synthesized and explicitly
characterized. Isolation of each coordi-
nation product through manipulation of
product equilibrium helps to guide ligand
design related to radiopharmaceutical ap-
plications.
J. Klenc, M. Lipowska,* A. T. Taylor,
L. G. Marzilli .................................... 1–9
Synthesis and Characterization of fac-
Re(CO) -aspartic-N-monoacetic
3
Acid:
Structural Analogue of a Potential Renal
9
9m
Tracer, fac- Tc(CO) (ASMA)
3
Keywords: Rhenium / Aminopolycarboxyl-
ate ligands / Ligand design / Isomer resol-
ution / Imaging agents
Eur. J. Inorg. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
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